Animal genomes are littered with conserved non-coding elements (CNEs)—most of which represent evolutionarily constrained cis-regulatory sequences—however, it is often not clear why these sequences are so exceptionally conserved, since anecdotal examples have shown that orthologous CNEs can have divergent functions in vivo (Strähle and Rastegar 2008; Elgar and Vavouri 2008). In an article recently published in Molecular Biology & Evolution, Ritter et al. compare the functional activities of 41 pairs of orthologous conserved non-coding elements (CNEs) from humans and zebrafish (2010). Interestingly, sequence similarity was found to be a poor predictor of which CNEs had conserved function. In contrast, the authors found that measuring transcription factor binding site change, instead of simple sequence divergence, improves their ability to predict functional conservation. Read more

In a recent opinion piece, Andreas Wagner tries to reconcile the tension between proponents of neutral evolution and selectionism (Wagner 2008). He argues that “neutral mutations prepare the ground for later evolutionary innovation”. Wagner illustrates this point using a network model of genotype-phenotype relationships (Wagner 2005). In a so-called ‘neutral network’, nodes correspond to distinct genotypes associated with the same phenotype and are connected by an edge if the respective genotypes differ only by a single mutation event (eg point mutation). Examples of neutral networks include different genotypes coding for RNA or protein structures. In this representation, highly connected networks correspond to robust phenotypes that are not very sensitive to changes in genotype. Wagner notes the zinc finger fold as an impressive example of a highly connected neutral network as its structure remains essentially the same even after mutating all but seven of its 26 residues to alanine. Read more

Gene duplications and mutations are central driving forces in the evolution of genomes. Genomes must be robust to such changes in order to be evolvable, and many studies have probed genome robustness using systematic gene knockouts or overexpression experiments. In a recent paper, Isalan et al. (2008) took a new approach to test the robustness of Escherichia coli gene circuitry by reconstructing gene duplication events by shuffling the promoter-ORF pairs for about 300 transcription factors and introducing 598 recombined pairs one-by-one into E. coli to rewire its transcriptional network. Surprisingly, ~95% of such additions are robustly tolerated, and some networks even exhibit greater fitness under various selection pressures. Moreover, the study shows that, in contrast to naive expectations, the introduction of positive or negative feedback loops has little effect on the protein expression levels of regulated ORFs. Read more

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The Seven Stones is the blog of Molecular Systems Biology, the open-access journal published by Nature Publishing Group and EMBO, which covers all aspects of the rapidly growing and interdisciplinary field of systems biology at the molecular level.